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Biochemical and molecular genetic studies were performed on the enzyme variants of two patients compound heterozygous for glucose phosphate isomerase (GPI) deficiency, both suffering from severe haemolytic anaemia. The enzymes of case 1 (GPI 'Zwickau') and case 2 (GPI 'Nordhorn' [25]), revealed reduced GPI activity and remarkable thermolability. Glucose-6-phosphate (Gluc-6-P) concentration was elevated 2.3 times in case 1 and 3.8 times in case 2. Sequencing the patients' GPI genes showed four different point mutations, two of them involving highly conserved amino acids. The c1039 C--T substitution, found in the gene of GPI 'Zwickau', has been described recently [30] and causes an Arg 347--Cys substitution close to the putative catalytic site. The second mutation in this case is a novel c1538 G--A substitution causing a Trp--stop mutation at position 513 apparently resulting in premature RNA degradation thus resulting either in a complete lack of protein or a protein which does not show GPI activity. In the gene of GPI 'Nordhorn' a c1028 A--G mutation was discovered, also previously described [1, 9] causing a Gln 343--Trp substitution. The second mutation was a novel splice site mutation at the border of intron 15 to exon 16: IVS15-(-2) A--C which leads to an aberrant splicing of exon 16, thus resulting either in a truncated and most likely inactive enzyme or in no protein at all.Biochemical and molecular genetic studies performed with the enzyme variants GPI 'Zwickau' and GPI 'Nordhorn' showed that in both cases the simultaneous occurrence of a single amino acid substitution affecting the active site, together with a nonsense mutation leading to the loss of major parts of the enzyme probably explains the severe clinical course of the disease.

Malignant ectomesenchymoma is a rare tumour that contains both ectodermal and mesenchymal elements. Only three patients with a manifestation in the cerebrum and clinicopathological data have been reported until now. We present a patient with an intracerebral ectomesenchymoma, review the literature and discuss currently available therapeutic options. In a 10-year-old girl, a left suprasellar temporo-parieto-occipitally localised tumour was diagnosed. The tumour was completely excised macroscopically in two surgical sessions. For the mesenchymal part of the tumour she subsequently underwent multidrug chemotherapy followed by radiation therapy. Considering the neuroectodermal element of the tumour, radiotherapy was applied to the craniospinal axis with a local boost. Therapy was tolerated well without any severe side effects. Six years from diagnosis, the patient is alive without a tumour relapse. Conclusion: Due to the sparcity of reported cases with malignant ectomesenchymoma, the role of adjuvant therapy is unclear. Multimodal therapy may be able to improve outcome.

In patients with β-thalassaemia major, frequent blood transfusions combined with desferrioxamine chelation therapy lead to an improved rate of survival. Endocrine disorders related to secondary haemosiderosis such as short stature, delayed puberty and hypogonadism are major problems in both adolescent and adult patients. A total of 32 patients with β-thalassaemia major undergoing treatment at the Children's Hospital, University of Gottingen were examined. Fourteen of these were short in stature. Growth hormone (GH) secretion was investigated in 13 patients exhibiting either a short stature or reduced growth rate. The stimulated GH secretion of 10 patients in this subgroup lay within the normal range. Studies of their spontaneous GH secretion during the night revealed that these patients had a markedly reduced mean GH and reduced amplitudes in their GH peaks. Low insulin-like growth factor (IGF)-I levels were seen in the growth-retarded thalassaemic patients. Eight were subjected to an IGF generation test and showed a strong increase in both IGF-I and insulin-like growth factor binding protein (IGFBP)-3 levels indicating intact IGF-I generation by the liver. Hypogonadotropic hypogonadism was found to be present in both the male and female patients with impaired sexual development. After priming with LH-releasing hormone (GnRH) per pump in 2 female and 5 male patients, no change in either their serum oestradiol or testosterone levels or in LH/FSH response to GnRH was observed suggesting that they were suffering from a severe pituitary gonadotropin insufficiency. Three male patients at the age of puberty but exhibiting short stature, low GH, low IGF-I and hypogonadism received low dose long-acting testosterone. After 3–12 months of therapy there was a marked growth spurt, higher nocturnal GH levels and an increase in both IGF-I and IGFBP-3. Conclusion Reduced GH secretion and low IGF-I in thalassaemic patients are related to a neurosecretory dysfunction due to iron overload rather than to liver damage. Hypogonadotropic hypogonadism is caused by the selective loss of pituitary gonadotropin function. In patients with both GH deficiency and hypogonadism, low dose sexual steroid treatment should be considered either as an alternative or an additional treatment before starting GH therapy.

A new triosephosphate isomerase (TPI) variant is described in an 8-year-old Turkish girl suffering from chronic haemolytic anaemia, myopathy and developmental retardation since early infancy. The enzyme activity profile revealed a generalized deficiency in erythrocytes, granulocytes, mononuclear blood cells, skeletal muscle tissue and cerebrospinal fluid. The concentration of enzyme substrate dihydroxyacetone phosphate was distinctly elevated. Biochemical examination showed accelerated enzyme deamidation, the first step in the normal catabolism of TPI during aging of the erythrocyte. The specific activity of the variant TPI, determined by antibody titration, was reduced to 61% of normal. Its heat stability was markedly decreased. Muscle biopsy and neuropsychological testing further clarified the pathogenesis of the disorder. A prevalent alteration of mitochondria similar to that seen in mitochondrial myopathy and an elevated amount of intracellular glycogen were found. The patient's retarded intellectual development was mainly due to impaired visual perception and sensory-motor co-ordination in addition to a lack of syllogistic reasoning. The findings indicate that the low TPI activity leads to a metabolic block of the glycolytic pathway and hence to a generalized impairment of cellular energy supply.

In a female child with severe combined immunodeficiency, pure red cell aplasia was observed which required regular transfusions of erythrocytes. Parvovirus B 19 DNA (but no antibodies) was detected in stored serum samples after the death of the patient. We suggest that the anaemia was a consequence of parvovirus infection which persisted for at least 2 years due to the immunodeficiency.

gamma-chain heterogeneity of haemoglobin F was studied in German full-term and preterm infants up to 12 months old. The A gamma T-gene frequency calculated was about 19%. In most cases with A gamma I-/A gamma T-chain heterogeneity A gamma I-chains predominated over A gamma T-chains. There was no difference between infants with or without the A gamma T-chain concerning haemoglobin F-concentration, F-cell percentage or G gamma-chain percentage. The G gamma-chains accounted for 69.2% +/- 3.3% (SD) of the total gamma-chains in full-term newborn infants with a decrease to 42.5% +/- 6.5% during the first 6 months. Comparison of the G gamma-chain decrease in preterm and in full-term newborn infants suggests a more pronounced decrease during extrauterine life than during the intrauterine course.